1. Field of the Invention
The present invention relates to a novel essentially pH neutral vaginal drug delivery system suitable for modified delivery of a therapeutically active material in the vaginal cavity which optimizes the chances for cure associated with the therapeutically active material. The vaginal drug delivery system comprises an essentially pH neutral emulsion having globules having two phases, an internal water soluble phase and an external water-insoluble phase or film, wherein the water-soluble interior phase contains a therapeutically active drug or drugs. One novel aspect of the vaginal drug delivery system is that the internal water soluble phase comprises an acidic buffered phase which is isotonic, hypertonic, or hypotonic. The present invention further relates to a method of treating a vaginal disorder using these drug delivery systems.
2. Description of the Related Art
One of the main disciplines of medicine is the management of the female reproductive system for the diagnosis, prevention, mitigation, treatment, and cure of diseases, as well as the prevention or enhancement of conception. Usually, this involves the direct delivery of active agents to the vaginal cavity and its environs.
Because the vaginal cavity is subject to conditions which render it a target for disease and infection, systems to effect the delivery of such agents are usually in the form of gels, foams, creams, suppositories, and quick dissolving tablets. These delivery systems, regardless of formulation or method of manufacture, have demonstrated some difficulty in their ability to deliver active agents in a controlled manner within the vaginal cavity for periods of three hours or longer. It is extremely difficult to deliver an active agent to this area for an extended period of time.
The vaginal cavity exhibits an aqueous environment containing secreting glands whose fluids create an acidic pH in the range of 4.5 to 5.5. The environment of the vagina is conducive to the growth of bacteria, fungi, yeast, and other microorganisms since it is warm, moist, and dark. Further, the physical structure is a vestibule for menstrual debris and residual seminal fluid from sexual intercourse, undesirable bacteria, fungi, yeast, and other microorganisms. The vaginal cavity is also subject to considerable physical deformation, such as during sexual intercourse or during the insertion of tampons.
Active agents which have pharmaceutical qualities have been developed and approved for use in the treatment of afflictions of the vaginal cavity and the prevention of conception. These active agents include fungicides, spermicides, etc. However, it has been difficult to achieve optimal potential effectiveness of these agents due to the inadequacy of known delivery systems. Systems which are presently approved or even suitable for use in the vaginal cavity have shown some difficulty in the release of a pharmaceutically active agent(s) for an extended period of time. This also is true of aesthetically oriented systems, such as acidifiers and deodorants.
The vast majority of gels, foams, creams, suppositories, and tablets that are presently used as vaginal delivery systems breakdown almost immediately following insertion into the vaginal cavity and have minimal bioadherence to the vaginal walls. This is believed to be due to their water miscibility and/or their lack of physical stability at 37° C. (body temperature). Thus, they exhibit limited effectiveness due to rapid, uncontrolled release of the active agents. Additionally, conventional dosage forms frequently discharge a leakage and drippage. To minimize this rapid leakage, most conventional dosage forms are administered at night just before the patient goes to sleep in a prone position.
A modified release system delivers the active agent to the sites of action, absorption, or use in a predetermined manner. This contrasts with conventional immediate release systems which require frequent repetitive dosing in order to achieve the desired level of active agent. An advantage of a modified release system is that the drug is administered fewer times a day than conventional systems since the drug level in the vaginal cavity is maintained at a constant rate. Additionally, the controlled release systems of the prior art do not affect the total number of days that are required to treat a condition.
Emulsions can be useful for the preparation of a modified release drug delivery system. Emulsions generally possess a high free energy protective barrier. In particular, emulsions having a relatively high ratio of water to oil and possessing high free energy are known in the art as High Internal Phase Emulsions (“HIPE's”). HIPE's have been used in various applications such as fuels, agricultural sprays, textile printing, foods, household and industrial cleaning, cosmetics and drugs, and fire extinguishers. HIPE's have also been used in producing polymeric foam-type materials. See, for example, U.S. Pat. No. 3,988,508 (“Lissant”); and U.S. Pat. No. 5,189,070 (“Brownscombe et al.”), each of which is hereby incorporated by reference in its entirety.
The most significant feature of known HIPEs is that the emulsions typically break down in the gastrointestinal and/or digestive tracts and lose internal phase energy, which causes the emulsion to coalesce into a continuous film on the mucosal membrane.
Several controlled release emulsions for use in the delivery of pharmaceuticals are known in the art. For example, U.S. Pat. No. 5,298,246 (“Yano et al.”), hereby incorporated by reference in its entirety, discloses oil-in-water emulsions for improving the absorbability of lipophilic drugs through oral administration. The emulsions are kept stable by adding a sodium phosphate isotonic buffer (pH 7.0).
U.S. Pat. No. 5,622,657 (“Takada et al.”), hereby incorporated by reference in its entirety, discloses a process for producing microparticle preparations having a prolonged release. These preparations can include a water-in-oil type emulsion and can be administered vaginally.
U.S. Pat. No. 5,733,939 (“Fuhrman et al.”), hereby incorporated by reference in its entirety, discloses a conventional drug delivery form for the treatment of mucosal inflammation, including the vaginal mucosa. This reference contemplates emulsions with a continuous gaseous or liquid fluorocarbon phase and a discontinuous aqueous phase in the form of gels.
U.S. Pat. No. 5,840,744 (“Borgman”), hereby incorporated by reference in its entirety, discloses a non-flowing metronidazole composition for the treatment of bacterial vaginosis. The disclosed metronidazole compositions can be buffered to an acidic pH. This reference contemplates water-in-oil emulsions wherein the metronidazole and buffer salts are dissolved or suspended in the oil phase ingredients.
U.S. Pat. No. 5,993,846 (“Friedman et al.”), hereby incorporated by reference in its entirety, discloses an emulsion for application to a mucosal surface, such as the vaginal mucosa. In particular, Friedman discloses lipid-in-water type emulsions containing drugs with enhanced bioadhesive properties.
U.S. Pat. No. 6,191,105 (“Ekwuribe et al.”), hereby incorporated by reference in its entirety, discloses microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents. The microemulsion comprises a water-in-oil emulsion. Ekwuribe discloses that the pH of the emulsions as a whole can be adjusted for compatibility with the nasal mucus membranes and eyes to which they are administered. Ekwuribe also contemplates vaginal administration of the disclosed formulations.
U.S. Pat. No. 6,294,550 (“Place et al.”), hereby incorporated by reference in its entirety, discloses a conventional drug delivery form for the treatment of female sexual dysfunction. This reference contemplates water-on-oil emulsions for vaginal delivery.
Nevertheless, broad spectrum use of the drug delivery systems described herein is precluded either because: (1) the known systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight therapeutics are not available; (3) the known systems exhibit poor stability and inadequate shelf life; (4) the known systems are difficult to manufacture; (5) the known systems fail to protect the active agent; (6) the known systems adversely alter the active agent; (7) the known systems fail to allow or promote absorption of the active agent; and/or (8) the known systems fail to deliver the active agent over a sufficiently extensive period of time.
Accordingly, an aspect of the presently claimed invention is to provide an essentially pH neutral vaginal drug delivery system comprising an essentially pH neutral emulsion having globules having two phases, an internal, acidic buffered water-soluble phase containing a therapeutically active drug or drugs and an external water-insoluble phase or film. This drug delivery system is advantageous in that it provides for the delivery of a therapeutically active drug or drugs in a modified manner in the vaginal cavity for an extended period of up to 168 hours. Accordingly, the drug delivery system optimizes the drug delivery efficacy, the therapeutic effects of the drug or drugs, and the chances for cure provided by the therapeutically active drug or drugs. The system may take the form of a multi-phase liquid or semi-solid which is easily introduced into the vaginal cavity but does not actively seep from this body cavity. It is further advantageous since it reduces the treatment period for active agents.
These and other aspects of the invention will be apparent from the detailed description and the claims.